Project Summary Nitrogen containing molecules are ubiquitous among compounds possessing significant biological activity due to their polarization, basicity, hydrogen-bonding ability and other physiological properties. This proposal describes a program in synthetic organic methodology aimed at developing rapid, stereoselective syntheses of complex nitrogen heterocycles using readily available precursors. The key to our approach is efficiency: we require rapid access to the starting material followed by high selectivity in the assembly of the components enabling two to three step syntheses of target molecules from readily available precursors. As part of this goal, we envision allowing the rapid assembly of complex biologically active heterocycles such as secu'amamine A, a compound related to the securinine/norsecurinine family of alkaloids that display antitumor, antimalarial, antibacterial, and CNS activity, the potent immunosuppressive FR901483, the important neurophysiological tools hydrohistrionicotoxin and perhydrohistrionicotoxin, and halichlorine, shown to selectively inhibit the induction of vascular cell adhesion molecule-1 (VCAM-1). The specific goals of this research are as follows: 1) develop the catalytic enantioselective alkenyl isocyanate and alkyne [2+2+2] cycloaddition;2) expand the scope of alkene partners to include di-, tri- and tetra-substituted partners;3) explore the nature and substitution patterns on the tether leading to diastereoselective reactions;4) pursue the rapid total synthesis of a variety of alkaloids using isocyanate [2+2+2] cycloadditions;5) investigate the use of new pi systems in [2+2+2] cycloadditions using our alkenyl isocyanate/alkyne coupling as a platform. The long-term impact of this science is to enable chemists to rapidly assemble alkaloidal structures with high efficiency. Project Narrative One of the most significant barriers to health-related research involving small molecules is the rapid assembly of therapeutic agents. This proposal seeks to develop new methods to synthesize alkaloidal frameworks using easily accessible precursors with high efficiency.